Methylenetetrahydrofolate reductase polymorphic variants in rectal cancer: significance for cancer risk and response to chemoradiotherapy

BackgroundMethylenetetrahydrofolate reductase (MTHFR) small nucleotide polymorphisms (SNPs) have been suggested as risk, prognostic, and predictive factors for colorectal cancer in various populations, but have not been validated so far. The aim of this study was to analyze the association of MTHFR C677T (rs1801133) and A1298C (rs1801131) small nucleotide polymorphisms with the risk of rectal cancer as well as the response to neoadjuvant chemoradiotherapy (nCRT) based on 5-Fluorouracil (5- FU)/leucovorin (LV) in the locally advanced setting. Patients and methodsA total of 102 patients with locally advanced rectal cancer (LARC) and 119 healthy controls were included in this case-control study. Restriction fragment length polymorphism analysis (PCR-RFLP) was used for MTHFR genotyping ResultsUsing dominant and recessive models, it was found that the MTHFR 667C allele and the 1298A allele were significantly associated with rectal cancer as low-penetrant factors. Combined genotype analysis highlighted the protective role of the 677CT/1298AC genotype and increased risk for rectal cancer development for carriers of 677CC/1298AA. Haplotype analysis indicated that carriers of haplotype 677C/1298A have an increased risk for rectal cancer development while the haplotype 677T/1298A has a protective role. No significant association with response to chemoradiotherapy was found ConclusionOur data point to MTHFR 667C allele and 1298A alleles as low-penetrant risk factors for rectal cancer in our population. To the best of our knowledge, this is the first study of this type performed on the Slavic population in the Western Balkan area which might be useful for future meta-analyses and the construction of genetic cancer risk prediction panels, as various population-based factors might also be significant in this setting.